title: High metal ion levels after use of the ASR™ device correlate with development of pseudotumors and T cell activation.
abstract: BACKGROUND
  Pseudotumors and immunologic alterations are reported in patients with elevated metal ion levels after resurfacing arthroplasty of the hip. A direct association of increased cobalt and chromium concentrations with the development of pseudotumors has not been established.
  
  
  OBJECTIVE
  We hypothesized that (1) patients with higher blood cobalt and chromium concentrations are more likely to have pseudotumors develop, (2) elevated cobalt and chromium concentrations correlate with increased activation of defined T cell populations, and (3) elevated metal ion levels, small implant size, cup inclination angle, and patient age are risk factors for the development of pseudotumors.
  
  
  METHODS
  A single-surgeon cohort of 78 patients with 84 Articular Surface Replacement(®) implants was retrospectively investigated. Between 2006 and 2010, we performed 84 THAs using the Articular Surface Replacement(®) implant; this represented 2% (84/4950) of all primary hip replacements performed during that period. Of the procedures performed using this implant, we screened 77 patients (99%) at a mean of 43 months after surgery (range, 24-60 months). Seventy-one patients were investigated using ultrasound scanning, and cobalt and chromium concentrations in whole blood were determined by high-resolution inductively coupled plasma mass spectrometry. Differential analysis of lymphocyte subsets was performed by flow cytometry in 53 patients. Results of immunologic analyses were investigated separately for patients with and without pseudotumors. Pseudotumors were found in 25 hips (35%) and were more common in women than in men (p = 0.02). Multivariable regression analysis was performed to identify risk factors for the development of pseudotumors.
  
  
  RESULTS
  Cobalt and chromium concentrations were greater in patients with pseudotumors than in those without (cobalt, median 8.3 versus median 1.0 μg/L, p < 0.001; chromium, median 5.9 versus median 1.3 μg/L, p < 0.001). The percentage of HLA-DR(+)CD4(+) T cells was greater in patients with pseudotumors than in those without (p = 0.03), and the proportion of this lymphocyte subtype was positively correlated with cobalt concentrations (r = 0.3, p = 0.02). Multivariable regression analysis indicated that increasing cobalt levels were associated with the development of pseudotumors (p < 0.001), and that patients with larger implants were less likely to have them develop (p = 0.04); age and cup inclination were not risk factors.
  
  
  CONCLUSIONS
  We found a distinct association of elevated metal ion concentrations with the presence of pseudotumors and a correlation of increased cobalt concentrations with the proportion of activated T helper/regulator cells. Thus, the development of soft tissue masses after metal-on-metal arthroplasty could be accompanied by activation of T cells, indicating that this complication may be partly immunologically mediated. Further investigations of immunologic parameters in larger cohorts of patients with metal-on-metal arthroplasties are warranted.
  
  
  METHODS
  Level III, therapeutic study. See the Instructions for Authors for a complete description of levels of evidence.
authors.affiliation: Department of Orthopaedics, Institute of Surgical Sciences, Uppsala University Hospital, Uppsala, Uppland, 75591, Sweden, nils.hailer@surgsci.uu.se.
authors.forename: Nils P
authors.initials: NP
authors.lastname: Hailer
authors.forename: Mats
authors.initials: M
authors.lastname: Bengtsson
authors.forename: Christina
authors.initials: C
authors.lastname: Lundberg
authors.forename: Jan
authors.initials: J
authors.lastname: Milbrink
mesh_terms: D000328:Adult; D000368:Aged; D019644:Arthroplasty, Replacement, Hip / Q000009:adverse effects / Q000295:instrumentation*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016009:Chi-Square Distribution; D002857:Chromium / Q000097:blood*; D002858:Chromium Alloys; D003035:Cobalt / Q000097:blood*; D005260:Female; D006104:Granuloma, Plasma Cell / Q000097:blood / Q000175:diagnosis / Q000209:etiology* / Q000276:immunology; D006684:HLA-DR Antigens / Q000097:blood; D006621:Hip Joint / Q000276:immunology / Q000601:surgery*; D006622:Hip Prosthesis; D006801:Humans; D007477:Ions; D016015:Logistic Models; D008213:Lymphocyte Activation; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D015999:Multivariate Analysis; D011474:Prosthesis Design; D012189:Retrospective Studies; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D002858:Chromium Alloys; D006684:HLA-DR Antigens; D007477:Ions; D002857:Chromium; D003035:Cobalt